Mice With Parkinson’s Disease Gene May Point the Way to New Treatments

NEW YORK (June 7, 2009) — Scientists at
Weill Cornell Medical College have developed a new mouse model of Parkinson’s
disease (PD) that successfully reproduces the impairments of movement and the
degenerative brain changes that occur in the human disease. Their research,
performed in collaboration with investigators at ColumbiaUniversity Medical Center, appears in the June 7 issue of the
journal Nature Neuroscience.

“Because this
new mouse model replicates the pathogenesis of human Parkinson’s disease so
closely, it promises to be a major boon to Parkinson’s research, both in terms
of basic science and drug development,” says Dr. M. Flint Beal, study co-author
and professor of neurology and neuroscience at Weill Cornell Medical College.
“While there are many treatments for the symptoms of PD, no current therapies
prevent the inevitable progression of the disease. One reason for the inability
to develop such therapies is that there has been no truly workable animal model
of the human disease. This new model will now address this critical
need.”

Earlier attempts to create
a mouse model for Parkinson’s continually fell short due to technological
limitations. Using a new transgenesis technology called BAC (bacterial
artificial chromosome) that allows researchers to insert large DNA fragments
into the genome, senior author Dr. Chenjian Li, assistant professor of neurology
at Weill Cornell Medical College, and his colleagues were able to introduce into
the mouse’s genome a mutant form of the LRRK2 gene — the most common genetic
cause of PD.

The Weill Cornell team
observed that the mice expressing the mutant form of the gene became very slow
to move as they became older, just like human PD patients. Remarkably, the mice
became able to move normally when treated with levodopa, the same drug that is
commonly used to treat human patients.

Further research by Drs.
Beal and Li and their labs revealed that the mice with impaired movement also
had impaired release of the brain neurotransmitter dopamine, just as it occurs
in the human disease. Dr. Robert Burke, the Alfred and Minnie Bressler Professor
of Neurology (in Pathology) at Columbia University Medical Center, and his
colleague Ms. Tinmarla Francis Oo, senior staff associate at Columbia University
Medical Center, further discovered that the dopamine deficit came from
disintegration, not of the dopamine neurons themselves, but of their axons, the
long, filament-like structures responsible for transmitting dopamine to distant
targets in the brain. Their insights, says Dr. Li, are helping us understand the
disease at a deeper level — something that will lead us to better treatments and
possibly even a cure for Parkinson’s disease.

There are currently two
standard types of treatment for Parkinson’s: medication and a surgical technique
called deep brain stimulation, which achieves similar results for some patients.
Neither approach, however, stops the progression of the disease as it lays waste
to the brain’s dopamine system and inexorably erodes key physical, cognitive and
psychological functions.

Says Dr. Li: “The new model
will provide scientists with an appropriate ‘stage’ on which to screen for
effective medications. It will also show us the disease in real time, allowing
us to track its progression at a cellular and molecular level. What we learn
will then feed back into the drug development
process.

“From a longer-term
perspective, this also gives us a picture-window into normal biology,” he
continues. “The new mouse model will provide an opportunity to investigate the
brain’s dopaminergic system, a brain circuit critical to movement, emotions and
drug addition.”

The study was supported by
the National Institute of Neurologic Disorders and Stroke, the Michael J. Fox
Foundation and the Parkinson’s Disease Foundation.

Parkinson’s is the second
most common neurodegenerative disease after Alzheimer’s. In its later stages, it
can be extremely disabling, both physically and mentally. The disorder not only
impairs the ability to initiate and sustain movement, but affects cognition and
mood as well. Aging, genetics, and environmental toxins are the main risk
factors for a disease whose prevalence is slated to rise dramatically as the
population ages. About 90 percent of the time, Parkinson’s is sporadic in
origin, meaning its cause is unknown. But 10 percent of cases run in families.